Clinical and regulatory development strategies for Shigella vaccines intended for children younger than 5 years in low-income and middle-income countries

Summary Shigellosis causes considerable public health burden, leading to excess deaths as well as acute and chronic consequences, particularly among children living in low-income and middle-income countries (LMICs). Several Shigella vaccine candidates are advancing in clinical trials and offer promise. Although multiple target populations might benefit from a Shigella vaccine, the primary strategic goal of WHO is to accelerate the development and accessibility of safe, effective, and affordable Shigella vaccines that reduce mortality and morbidity in children younger than 5 years living in LMICs. WHO consulted with regulators and policy makers at national, regional, and global levels to evaluate pathways that could accelerate regulatory approval in this priority population. Special consideration was given to surrogate efficacy biomarkers, the role of controlled human infection models, and the establishment of correlates of protection. A field efficacy study in children younger than 5 years in LMICs is needed to ensure introduction in this priority population.


Appendix
Box 1: Summary assumptions and inter-dependencies for regulatory approval of a multivalent travellers' vaccine, intended for use in high-risk adults in HICs: ▪ The methodology is harmonised across the S. flexneri 2a and S. sonnei CHIMs, the O-Ag IgG ELISA assays for all vaccine serotypes are standardised, and an international reference serum against all vaccine serotypes is established; ▪ The CHIM studies consider a 3-or 6-month efficacy assessment time point based on precedence of the Vaxchora vaccine approval approach [38,39].▪ Co-administration studies with other common travel vaccines may need to be conducted to support non-interference, pre-or post-licensure.▪ The development of CHIM for the additional Shigella flexneri serotypes (3a and 6) may serve to further de-risk investment in product development of a multivalent vaccine; however, demonstration of efficacy for 2 serotypes in a CHIM is likely considered sufficient to support licensure of the multivalent vaccine for high-risk adults in HICs, assuming similar immune responses against the other serotypes are demonstrated.
Box 2: Summary assumptions and dependencies for a traditional development and regulatory approval pathway in infants and young children under 5 years of age in LMIC countries ▪ A multi-country, multi-region epidemiology study is needed to establish the site-specific incidence of moderate or severe diarrhoea or dysentery caused by Shigella, in children under the age of 36 months, as well as to assess serotype prevalence.The incidence and serotype data are foundational to clinical trial design, including the sample size, and the Shigella force of infection.These studies are ongoing [53].▪ The efficacy will likely only be measurable against a composite endpoint of all Shigella vaccine serotypes, or at most, 1 or 2 Shigella serotypes (likely S. flexneri 2a and/or S. sonnei); however, serum IgG against the O-Ag could be explored as an immune marker to infer protection from the other strains.If this study validates a serum IgG threshold against O-Ag for S. sonnei or S. flexneri 2a as a correlate of protection, future O-Ag-based Shigella candidates could be licensed on the basis of safety and non-inferiority in an immunogenicity study in the target population.▪ Compatibility of the vaccine within the schedule and delivery setting of the expanded programme of immunization (EPI) will be crucial for cost-effectiveness, which is a pre-requisite for global policy recommendation and country-level introduction.
Box 3: Summary assumptions and dependencies for conditional marketing authorisation in infants and young children under 5 years of age, for use in non-Gavi countries: ▪ The public health need for a Shigella vaccine is considered an emergency, and the interim data are sufficiently compelling to qualify for the CMA pathway.
Table 1: Summary of potential Shigella vaccine licensure strategies, and their relative benefits, limitations, and risks.
▪ The phase IIb component of the study has sufficient subjects to support a safety database of at least n=3,000.▪ The phase IIb/phase III study is a multi-country study in areas of high Shigella incidence; this would require regional regulatory co-ordination and oversight.▪ Efficacy data from CHIM would be supportive in CMA scenario, although CHIM data would be from adults.

Regulatory
Limited to vaccines where there is a compelling public health need, in situations where interim efficacy is exceptional, and where the anticipated clinical benefits far outweigh the potential risks.▪ Regulators will be unlikely to approve through CMA without commitment to the continuation of the efficacy study, per protocol.▪ High-risk strategy for developers.▪ Will limit initial availability to the private market, and lead to inequitable access